The form of drug resistance is severe, how should the course of antibiotics for gram-negative bacilli infection be adjusted?

*Read only for medical professionals.
The field of GNB infections is facing a strong trend towards shorter antibiotic courses
.

Gram-negative bacilli (GNB) infections account for a large proportion of intra-abdominal infections (IAIs), bloodstream infections (BSIs), and hospital-acquired or ventilator-associated pneumonia (HAP/VAP), often developing into critically ill patients
.

To avoid inappropriate overuse of antibiotics in the fight against antimicrobial resistance, interventions to limit antibiotic use are needed, including avoiding overuse of broad-spectrum antibiotics, prolonged treatment courses, and off-label use of antibiotics
.

Unnecessarily prolonging antibiotic courses not only promotes the emergence of antibiotic resistance, but also prolongs hospital stays, healthcare costs and the risk of antibiotic-related adverse events
.

A prolonged course of antibiotics may have adverse effects on patients and the population as a whole, while inappropriately shortening the course of antibiotics may increase the risk of treatment failure
.

Therefore, the correct course of antibiotics needs to be determined
.

In 2020, Jean-Francois Timsit et al.
published a review "Duration of antimicrobial therapy for Gram-negative infections" in Current Opinion in Infection Diseases, focusing on the latest knowledge on the safety of short courses of antibiotic therapy for GNB infections
.

1.
Various effects of short-course antibiotic treatment 1.
Effects on antibiotic resistance Studies have found that shortening the course of exposure to broad-spectrum antibiotics can effectively prevent the emergence of resistance
.

A 2003 trial of 8-day VAP versus 15-day VAP therapy by Chastre et al.
has found an increased risk of multidrug-resistant bacteria in patients with recurrent infections in the 15-day treatment group
.

More recently, a retrospective study by Ong et al.
found that meropenem exposure was associated with meropenem resistance in Pseudomonas aeruginosa strains in monitored respiratory samples from critically ill patients (compared with meropenem in patients not exposed to meropenem).
The adjusted hazard ratio was 11.
1)
.

In a cohort study of 7118 critically ill patients, Teshome et al found that the emergence of anti-pseudomonas β-lactam drug use-related resistance was associated with an increase in the course of antibiotics per day, suggesting that the precise determination of the necessary course of treatment may be necessary.
importance
.

2.
Effects of shorter duration of treatment on clinical efficacy There are several trials aimed at investigating shorter duration of antibiotics while maintaining good clinical efficacy
.

(1) The safety of a short-term 8-day course of VAP in Enterobacteriaceae for pulmonary infection is mainly based on the randomized trial of Chastre et al
.

The trial determined that an 8-day course of VAP was as effective as long-term treatment in terms of mortality and relapse rates
.

Subsequent studies and meta-analyses further confirmed the non-inferiority of a short course of treatment, and as such, 8-day treatment for Enterobacteriaceae VAP is recommended in both the US and European guidelines
.

The course of non-fermented GNB-VAP remains a matter of debate
.

In the trial of Chastre et al.
, although duration of mechanical ventilation and 28-day mortality did not differ between the 8- and 15-day course groups, the nonfermenting GNB-VAP subgroup had a higher rate of infection recurrence during the 8-day short course , so US guidelines recommend that the course of non-fermented GNB-VAP should be 15 days
.

A meta-analysis confirmed that there was no difference in mortality between short courses of treatment in the subgroup of nonfermented GNB, and other studies provided additional data to support the safety of short courses of antibiotics for nonfermented GNB-VAP
.

The ProVAP study mainly involved non-fermented GNB-VAP, and there were no differences in relapse and mortality rates between antibiotic discontinuation and control groups
.

In a retrospective cohort study of Pseudomonas aeruginosa VAP, antibiotic duration was not associated with a higher risk of treatment failure
.

Ongoing iDIAPASON trial, which hopes to fill the gap of a randomized controlled trial dedicated to nonfermented GNB-VAP, aims to enroll 600 patients with P.
aeruginosa VAP for 90-day mortality and P.
aeruginosa during ICU stay VAP recurrence rates (within 90 days) were combined as the primary endpoint to assess non-inferiority of 8- and 15-day courses of antibiotics
.

Further shortening the duration of VAP antibiotics to less than 8 days is the aim of the few ongoing randomized trials
.

The REGARD-VAP trial is enrolling ICU patients with suspected VAP to assess the noninferiority of 5-7 days of antibiotic therapy compared to long-term therapy (at least 8 days)
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The DATE trial (courses of antibiotic therapy for early VAP) is comparing 4- and 8-day courses of early VAP in patients following ICU surgery
.

An alternative to a fixed course of antibiotics strategy is the use of an adjustable course of antibiotics discontinuation based on clinical criteria and/or biomarkers
.

Procalcitonin (PCT), the most extensively studied biomarker of antibiotic discontinuation in ICU patients, was found to be effective in reducing antibiotic exposure in the ICU
.

A recent study on VAP confirmed that the PCT-guided antibiotic discontinuation algorithm was associated with shorter antibiotic courses in VAP (mean course of 8 days versus 9.
5 days in the control group), however, the intervention in the study did not reduce the course of antibiotics to within 8 days
.

(2) Intra-abdominal infection Some simple intra-abdominal infections can be treated without any antibiotics after surgery if adequate source control is achieved
.

Randomized trials of uncomplicated acute cholecystitis and appendicitis have shown that it is safe to discontinue antibiotics immediately after surgery to effectively control the source of infection
.

The 2018 Tokyo guidelines recommend antibiotic treatment after source control of acute cholangitis, with a recommended course of 4-7 days
.

However, in a recent retrospective study, very short treatment (3 days or less, median 1.
5 days) compared with longer treatment (4 days or less, median 7 days) ) is not associated with a higher risk of failure
.

However, randomized trials are needed to determine whether the course of antibiotics for acute cholangitis can be further shortened, or even to assess whether it is feasible to discontinue antibiotic therapy immediately after biliary drainage
.

For complex IAIs with adequate source control, the duration of antibiotics is currently recommended for 4-7 days, and the data are mainly based on the STOP-IT randomized controlled trial
.

The trial showed no increased risk of failure with the 4-day treatment compared with the longer treatment duration
.

The DURAPOP trial, a step toward short-term treatment of critically ill patients with postoperative peritonitis, showed no difference between 8- and 15-day antibiotic courses, although this conclusion was tempered by more percutaneous drainage in the 8-day group
.

In fact, in recent retrospective studies, the actual course of antibiotics appears to remain longer, which may simply reflect slow changes in clinical practice
.

(3) Evidence for short-term treatment of gram-negative infections in bloodstream infections is weaker in subgroups of patients with bacteremia who are often excluded from trials investigating the duration of treatment at specific sites of infection
.

In addition to the lack of evidence on primary bloodstream infections, antibiotic treatment is often extended to 14 days or longer due to limited data on GNB bacteremia
.

Retrospective cohort studies have brought conflicting results
.

Three propensity-score-matched retrospective cohort studies of Enterobacteriaceae bloodstream infections in 2017 and 2018 compared short- and long-term antibiotic courses
.

In these studies, the cutoff between short and long term was set at 9-10 days
.

The study by Nelson et al.
found a higher rate of 90-day treatment failure (defined as death or recurrence of infection) associated with short-term treatment, while the studies by Chotiprasitsakul et al.
and Sousa et al.
showed that short- and long-term antibiotic courses were associated with mortality or recurrence.
No significant difference
.

Regarding nonfermented GNB, a similarly designed P.
aeruginosa BSI study showed no statistically significant difference in 30-day mortality or infection recurrence, with a treatment failure rate of 14 in the short-course group (7-11 days, median 9 days) %, compared with 13% in the long-term group (12-21 days, median 16 days)
.

Yahav et al recently published a multicenter noninferiority randomized controlled trial involving 604 patients, and the results support the use of a 7-day short-term treatment for uncomplicated GNB bacteremia
.

On day 7 of antibiotic treatment, hospitalized patients who had improved early clinical outcomes were randomly assigned to receive 7 or 14 days of treatment
.

Short-term treatment was non-inferior to long-term treatment based on the main study results of 90-day all-cause mortality, recurrence, complications, readmission or prolonged hospital stay
.

The length of hospital stay was similar in the two groups, however, the median time to return to randomization was 1 week shorter in the short-term group (3 weeks in the long-term group)
.

In Yahav's trial, the numbers of these two types of patients were small, and the results of the study that produced severe patients and nonfermentative GNB bacteremia need to be interpreted with caution
.

The BALANCE trial (course of bacteremia antibiotics actually needed based on clinical efficacy), scheduled to end in 2022, will provide further data on the safety of short-term antibiotic therapy for GNB bacteremia and whether it can be extended to critically ill patients
.

BALANCE recruited 3600 patients with gram-negative or gram-positive bacteremia (excluding S.
aureus and S.
ludens), randomized to receive a 7-day or 14-day course of antibiotics, and used 90-day survival as the primary outcome, non-inferiority The efficacy margin was set at +4%
.

Secondary outcomes included hospital and ICU mortality and length of stay, relapse rate, antibiotic-free days, C.
difficile infection, antibiotic allergy, adverse events, and emergence of resistant bacteria
.

The large sample size of the BALANCE study is expected to yield key insights into subgroups of nonfermentative BSI and nonurinary BSI
.

2.
Prefer an adjustable course of antibiotics? A shortened course of antibiotics may be fine for some patients, while others will benefit from a longer course of antibiotics
.

The PIRATE research group conducted a point-of-care, informatics-based randomized controlled trial to reduce antibiotic overuse in Gram-negative bacteremia
.

The principle of the trial is to personalize the course of antibiotics based on the early evolution of clinical and biological variables to safely shorten antibiotic exposure in patients who show early signs of improvement
.

The trial by von Dach et al randomized 504 patients with GNB bacteremia into three groups: a 14-day "fixed-long" course of antibiotics, a 7-day "fixed-short" course of antibiotics, and an "individualized guide" course of antibiotics (individualized guidance was Discontinuation algorithm based on clinical parameters and CRP levels)
.

Although clinical failure rates were low in all groups, 7-day treatment and CRP-guided treatment were non-inferior to 14-day treatment in terms of clinical failure rates
.

An individualized course of antibiotics may be a way to reduce overall antibiotic use without compromising the safety of individualized treatment
.

Future studies are needed to evaluate the safety of new treatment discontinuation algorithms, as well as to shorten the median antibiotic course and global antibiotic consumption
.

3.
When should short courses of antibiotics not be used? Some situations require additional attention to the choice of course of antibiotics
.

1.
Lack of adequate source control When considering a short course of antibiotics, source control is very important, especially for IAI and catheter-related BSI
.

Therefore, source control should be prioritized before considering short-term antibiotic therapy
.

For IAIs in particular, a comprehensive collaboration with the surgeon helps reduce treatment time
.

2.
Studies of the course of antibiotic therapy for immunodeficiency typically exclude immunocompromised patients because the innate and adaptive immune systems are critical for infection recovery and immunodeficiency can interfere with the clinical outcome of GNB infection
.

However, the retrospective study by Fabre et al.
included the majority of immunocompromised P.
aeruginosa BSI patients (65%), and there was no statistical difference between the short- and long-term treatment groups, although the course of antibiotics in the short-term treatment was already quite long ( 7-11 days, median course of treatment 9 days)
.

And, although data on the course of antibiotics in immunocompromised patients are needed, each immunodeficiency (neutropenia, HIV infection, antibody deficiency, etc.
) is so specific that it is difficult to establish a homogeneous patient population to study
.

3.
Duration of multidrug-resistant/extensively drug-resistant gram-negative bacteria For multidrug-resistant/extensively drug-resistant (MDR/XDR) GNB, is there a reason to prolong the duration of antibiotic treatment? There is currently a paucity of studies specifically targeting the course of treatment for drug-resistant GNB
.

In the study by Yahav et al.
, in a subgroup of 109 patients with MDR-GNB-BSI, including 105 with extended-spectrum beta-lactamase-producing Enterobacteriaceae, treatment failure was observed in 39 of 58 patients in the short-term treatment group ( 67.
2%), 34 of 51 patients in the long-term treatment group (66.
7%) failed treatment, and these patients did not appear to benefit from a longer course of treatment
.

Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with higher mortality compared with carbapenem-susceptible Enterobacteriaceae (CSE)
.

In the site of XDR-GNB infection, the limited bactericidal activity of antibiotics as well as the tissue concentration of antibiotics may lead to prolonged treatment duration
.

Although many studies have focused on the choice of antibiotic regimens for CRE, the issue of treatment duration has not been addressed in studies
.

Conclusions: The GNB infection field is facing a strong trend towards shorter antibiotic courses
.

Recent advances have found that, including uncomplicated Enterobacteriaceae BSI, a 7-day course is safe, whereas less data are available on nonfermented GNB BSI
.

A promising innovative approach is the individualized treatment course based on an on-treatment discontinuation algorithm, which could allow for further shortening of the treatment course for some patients
.

However, there are conditions that must be carefully managed to ensure safety for short-term antibiotic courses, including patient immunodeficiency, infection-resistant GNB, and inadequate source control
.

This article is only used to provide scientific information to medical and health professionals, and does not represent the platform's position.
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